A blind, prospective evaluation of the incidence and course of isoniazid-associated liver injury was made in 358 hospitalized men. The men were psychiatric patients during one year of tuberculosis preventive therapy. Blood samples were obtained at monthly intervals from the patients, the majority of whom were taking isoniazid. When the data were analyzed at the end of the year, a strikingly increased incidence of abnormal serum transaminase (SGOT) and bilirubin values was found among the isoniazid recipients. However, most subjects demonstrating biochemical evidence of hepatic injury recovered completely while continuing to take isoniazid and did not progress to clinically overt hepatitis. The mechanism underlying this adaptation to isoniazid injury is unknown. No serum antibodies against isoniazid could be demonstrated, and no correlation was found between the presence of antinuclear antibodies or elevated isoniazid plasma concentrations and the occurrence of hepatic injury. These data support the view that hepatotoxic metabolities of isoniazid may be responsible for the liver injury.